Periodontal tissue destruction involves a complex series of events including colonization of the tooth surface and gingival sulcus by a diverse array of bacteria. This is thought to be followed by penetration of the sulcular epithelium and the elicitation of a host-response in the underlying connective tissue. A prominent bacterium in periodontal infections is P. gingivalis. Considerable efforts has been spent examine the effect of P. gingivalis and its virulence factors in vitro and on it's capacity to colonize epithelium. However, surprisingly little is known about the in vivo response to P. gingivalis in connective tissue and to specific P. gingivalis factors that are thought to modulate the host response, fimbriae and LPS. The goal of this proposal is to focus on these two specific P. gingivalis components. We will test the hypothesis that fimbriae and LPS play a cental role in activating the innate host response and in mediating PO. gingivalis induced tissue destruction. This will be accomplished by quantitative analysis of the inflammatory response, soft tissue necrosis, osteoclast activity and survival of bacteria in vivo. Mechanistic studies will be undertaken by blocking the function of fimbriae or LPS in vivo, and then determining if this causes a significant change in the host response. Most importantly, we will determine if the host-response to P. gingivalis and P. gingivalis fimbriae and/or LPS is exaggerated in diabetic mice compared to non-diabetic littermates. These analysis will focus on the difference diabetics and normals with respect to induced neutrophil/monocyte chemotaxis and osteoclastogenesis (representing primary outcome variables) and cytokine/chemokine induction, lymphocyte recruitment, soft tissue necrosis, and bacterial survival and connective tissue (representing secondary outcome variables.)